The intracellular second messenger cyclic ADP-ribose (cADPR) induces Ca(2+) release through the activation of ryanodine receptors (RyRs). Moreover, it has been suggested that cADPR may serve an additional role to modulate sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) pump activity, but studies have been complicated by concurrent actions on RyR. Here, we explore the actions of cADPR in Xenopus oocytes, which lack RyRs. We examined the effects of cADPR on the sequestration of cytosolic Ca(2+) following Ca(2+) transients evoked by photoreleased inositol 1,4,5-trisphosphate (InsP(3)), and by Ca(2+) influx through expressed nicotinic acetylcholine receptors (nAChR) in the oocytes membrane. In both cases the decay of the Ca(2+) transients was accelerated by intracellular injection of a non-metabolizable analogue of cADPR, 3-Deaza-cADPR, and photorelease of cADPR from a caged precursor demonstrated that this action is rapid (a few s). The acceleration was abolished by pre-treatment with thapsigargin to block SERCA activity, and was inhibited by two specific antagonists of cADPR, 8-NH(2)-cADPR and 8-br-cADPR. We conclude that cADPR serves to modulate Ca(2+) sequestration by enhancing SERCA pump activity, in addition to its well-established action on RyRs to liberate Ca(2+).